CN101189030A - Method for terminal sterilization of transdermal delivery devices - Google Patents

Method for terminal sterilization of transdermal delivery devices Download PDF

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Publication number
CN101189030A
CN101189030A CNA2006800192630A CN200680019263A CN101189030A CN 101189030 A CN101189030 A CN 101189030A CN A2006800192630 A CNA2006800192630 A CN A2006800192630A CN 200680019263 A CN200680019263 A CN 200680019263A CN 101189030 A CN101189030 A CN 101189030A
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microprojection member
radiation
influenza vaccines
packing
coating
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S·塞勒斯
Y·马
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Alza Corp
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Alza Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/10—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
    • A61K41/17—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/08—Radiation
    • A61L2/081—Gamma radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/08—Radiation
    • A61L2/087—Particle radiation, e.g. electron-beam, alpha or beta radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20—Gaseous substances, e.g. vapours
    • A61L2/206—Ethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0061—Methods for using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Medicinal Preparation (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method and system for providing a terminally sterilized transdermal influenza vaccine delivery device. A microprojection member having a plurality of stratum corneum- piercing microprojections is coated with an influenza vaccine-formulation and exposed to sufficient radiation to sterilize the microprojection member while retaining sufficient potency of the influenza vaccine. Preferably, the microprojection member is sealed in packaging, such as a foil pouch. Also preferably, a retainer ring and adhesive are included within the packaging. The sterilizing radiation can be gamma radiation or e- beam, preferably delivered in a dose in the range of approximately 7 - 21 kGy. Also preferably, the irradiation is performed from -78.5 - 25 DEG C. In preferred embodiments, the radiation is delivered at a rate greater than 3.0 kGy/hr.

Description

The final sterilization method of transdermal delivery apparatus
Technical field
[0001] the present invention relates generally to transdermal reagent delivery system and method.Particularly, the present invention relates to being used to send the transdermal apparatus method of disinfecting of influenza vaccines.
Background technology
[0002] influenza is a kind of very complicated public health problem, requires every kind of Strain design specificity vaccine at expection usually.Influenza virus shows surface glycoprotein, hemagglutinin and the neuraminic acid enzymic change that the seller can't expect, thereby has different antigen actives.These variations finally cause forming new influenza strain.
[0003] the significant antigen that the immunity of influenza virus is subjected to this virus change and this localized infection in the restriction of respiratory system mucosa.That can obtain at present and licensed-in influenza vaccines or based on complete inactivation of viruses or based on the virus surface glycoprotein.
[0004] influenza virus comprises two kinds of surface antigens: neuraminidase and hemagglutinin, thus the two changes and causes influenza to have height antigen changing.Hemagglutinin is strong immunogen, and is most important antigen when the serological specificity of definition different virus strain.Hemagglutinin molecule (75-80kD) comprises a lot of antigenic determinants, and some of them are in the zone (strain specificity determiner) that sequence variation takes place in the homophyletic not, and other are in many HA molecules is (common determiners) in the common zone.Correspondingly, hemagglutinin provides useful basis for forming effective influenza vaccines.
[0005] as known in the field, skin is not only the physical barriers that the protection health is avoided outside harm, also is immune integral part.Give birth to epidermis alive and the resident's cellular component of corium and the set of body fluid component (humeral constituent) of immunologic function and acquisition immunologic function in the immunologic function of skin is derived from and has, be generically and collectively referred to as skin immune system.
[0006] one of most important composition of skin immune system is langerhans cell (Langerhan ' scell), and this is the cell of finding in the epidermis of living that specific antigen is provided.LC is because its dendron extensive branch connection between the cell around forms semicontinuous network in the epidermis of living.The normal function of LC is to detect, catch and provide antigen to arouse the immune response to the invasion pathogen.LC by make the internalization of upper epidermis antigen, be transported to regional skin draining lymph node (regionalskin-draining lymph node) and the antigen that will handle offers the T cell and carries out its function.
[0007] effectiveness of skin immune system is the reason at successful, the safe vaccination strategies of skin.With the inoculation that the antismallpox vaccine of reduced activity carries out, successfully in the whole world, eradicated fatal variola disease by prick skin.The various vaccines of standard I M dosage of intradermal injection 1/5-1/10 have been induced immune response effectively with numerous vaccines.
[0008] therefore, transdermal delivery just becomes the administration activating agent, hemagglutinin antigen especially, feasible replacement method, these activating agents otherwise will need to send by subcutaneous injection or venous perfusion.Term " transdermal " is a general name as used herein, (for example refer to active agent delivery, therapeutic agent is protein for example, or immune-active agent vaccine for example) passes skin to local organization or systemic circulation system, and obviously do not cut or pierce through skin, for example cut or with subcutaneous injection needle-penetration skin with scalpel.Therefore, transdermal reagent is sent in Intradermal, intradermal and the epidermis that comprises via passive diffusion and is sent, and for example sends electricity (for example ionotherapy) and ultrasonic (for example phonophoresis) based on extra power.
[0009] more common passive transdermal reagent delivery system generally includes the medicament reservoir that contains the high concentration activating agent.This bin is suitable for and contact skin, and it can make medicament diffuse through patient's skin and enter bodily tissue or blood.
[00010] this area is well-known, and the transdermal drug flow depends on the size of skin, drug molecule and physical/chemical and across the Concentraton gradient of skin.Because skin is to the hypotonicity of many medicines, the application of transdermal delivery is restricted.This hypotonicity is horny layer due to mainly, promptly outermost cortex, and it is made up of flat dead cells that is filled with keratin fiber (being keratinocyte) that double-layer of lipoid surrounds.This high-sequential structure of double-layer of lipoid makes horny layer impermeable relatively.
[00011] a kind of common methods of the passive transdermal diffusion of increase medicament flow comprises that mechanical system pierces through most external cortex (one or more layers), to form microchannel (micropathway) in skin.After deliberation mechanical system pierce through or destroy most external skin in skin, to form the many technology and the apparatus of passage.Exemplary is at U.S. patent No.3, disclosed medicine delivery device in 964,482.
[00012] uses small skin-piercing element and be disclosed in U.S. patent Nos.5 with other system and the device that improves transdermal reagent and send, 879,326,3,814,097,5,250,023,3,964,482, the No.25 that announces once more, 637 and PCT announce WO 96/37155, WO96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO 98/00193, WO99/64580, WO 98/28037, WO 98/29298 and WO 98/29365; This paper is all incorporated by reference with all documents.
[00013] disclosed system and device use the element that pierces through of various shapes and size to pierce through most external cortex (being horny layer).The disclosed element that pierces through vertically extends from thin flat element, for example liner or sheet usually in these lists of references.In some these apparatus to pierce through element very little, the Microprojection length that some has only is about 25-400 micron, Microprojection thickness only is about 5-50 micron.These are small pierces through/and cutting element obtains corresponding little microslits/microcuts, promoted to send by its transdermal reagent in horny layer.
[00014] disclosed system further comprises the bin of storing medicament usually, and medicament is passed the delivery system that horny layer shifts from bin, for example pitches by the hollow of apparatus itself.An example of this apparatus is disclosed among the WO 93/17754, and it has the liquid preparation bin.Yet, impel liquid preparation to pass small tube element must for this bin pressurization, enter skin.But the shortcoming of these apparatuses comprises and is used to increase the additional complexity and the expense of fluid under pressure bin and owing to have the complexity of pressure-driven delivery system.
[00015] as at U.S. patent application No.10/045, disclosed in 842, it is all incorporated by reference, and being coated in activating agent to be sent on the Microprojection rather than being included in also is possible in the physical storage device.This has eliminated independently physical storage device and exploitation are used for the particular agent preparation of described bin or necessity of compositions.
[00016] as noted, hemagglutinin antigen is only sent via intravenous route at present.Therefore, need provide a kind of drug delivery system that can promote the transdermal administration influenza vaccines.
[00017] the non-disinfection standard that must satisfy strictness through the intestinal pharmaceutical preparation such as hemagglutinin antigen.A kind of conventional method that guarantees sterilized articles therefrom is a sterile preparation.But, consuming time usually, the consumption labour and extremely expensive of requirement who in whole process of preparation, keeps gnotobasis.
[00018] the potential attractive alternative of sterile preparation is a sterilized articles therefrom when preparation process finishes.For stable micromolecule, terminal disinfection (terminal sterilization) is by daily employing.Unfortunately, this method is a great challenge for more unsettled bio-pharmaceutical goods.Especially, complicated biomolecular structure must protectedly prevent to degenerate such as hemagglutinin antigen, thus the therapeutic activity of keeping.
[00019] in U.S. Patent No. 6346216 and 6171549, Kent discloses and has adopted the low exposure rate various biomolecule of sterilizing.But these are taught in solution does not all have successfully at the specified conditions aspect of vaccine or transdermal delivery apparatus.Kent does not also make any discussion to packing to the influence of goods stability, but concentrates in the room temperature irradiation.
[00020] so, target of the present invention provides the method that is used for will being used to easily sending the transdermal sterilization of instruments of influenza vaccines.
[00021] another target of the present invention provides and compares the higher transdermal delivery system sterilization method of cost effectiveness with sterile preparation.
[00022] influenza vaccines that provide being used for transdermal delivery of another target of the present invention carry out finally pasteurised method.
[00023] another target of the present invention provides the terms of packing that is used for the transdermal delivery apparatus, and it is used for making the stability of disinfecting process influenza vaccines to obtain optimization.
[00024] the transdermal apparatus that provides being used to send influenza vaccines of another target of the present invention carries out finally pasteurised method, and wherein said vaccine keeps the activity of obvious degree.
Summary of the invention
[00025] according to above-mentioned target and the target that below will mention and become apparent, the method and system of transdermal influenza vaccines delivery device of being used for finally sterilizing comprises the steps: to provide the Microprojection member, and described Microprojection member is exposed in the radiation that is selected from gamma-radiation and electron beam, wherein said radiation is enough to the sterilization assurance level (sterility assurancelevel) that reaches required.Described Microprojection member comprises a plurality of cuticular Microprojections with biocompatible coating that are used to pierce through, and described coating is provided with at least a influenza vaccines.Preferably, described Microprojection member is sealed in and is used in the packing of irradiation protection vaccine.In one embodiment, described packing comprises paper tinsel bag (foil pouch).
[00026] in one aspect of the invention, described Microprojection member is installed on the keeper ring (retainer ring) before in being sealed to described packing.In preferred embodiments, in packages sealed, include keeper ring and binding agent.
[00027] the present invention comprises that also the temperature by adjusting the irradiation generation reduces the degeneration of influenza vaccines in disinfecting process.In one embodiment, the Microprojection member approximately-the temperature irradiation of 78.5-25 ℃.The outthrust member can shine under the dry ice condition at-78.5 ℃.In another embodiment, the Microprojection member is in approximately 0-25 ℃ temperature range internal radiation.In another embodiment, the Microprojection member is in approximately 20-25 ℃ ambient temperature irradiation.
[00028] according to the present invention, the Microprojection member receives the exposure dose of about 7kGy.In another embodiment, dosage is about 14kGy.In another embodiment, dosage is about 21kGy.
[00029] in another embodiment, the present invention includes the Microprojection member is exposed in the irradiation of speed greater than about 3.0kGy/hr.
[00030] in other embodiment of the present invention, the Microprojection member is exposed to and is enough to obtain sterilization and guarantees that level is 10 -3Radiation in.
[00031] in other embodiments, the present invention is transdermal influenza vaccines delivery systems, comprise the Microprojection member, described member comprises a plurality of cuticular Microprojections of patient that are used to pierce through, this Microprojection member is provided with biocompatible coating, and described coating is formed by the coating formulation with at least a influenza vaccines; With the packing that is used to protect vaccine of sealing around described Microprojection member, wherein said packages sealed has been exposed in the radiation so that described Microprojection component sterilization.In one embodiment, described packing comprises the paper tinsel bag.Preferably, binding agent and described Microprojection member are sealed in the packing together.Same preferred, described Microprojection member is installed on the keeper ring.
[00032] in other embodiments; the present invention is the transdermal system that is used to send influenza vaccines; comprise Microprojection member, aqueogel and packing; described Microprojection member comprises a plurality of cuticular Microprojections of patient that are used to pierce through; described aqueogel and the connection of described Microprojection member also have at least a influenza vaccines; with the protection vaccine, wherein said packages sealed has been exposed under the radiation so that the Microprojection component sterilization described packing around described Microprojection member sealing.
[00033] in other embodiments; the present invention is the transdermal system that is used to send influenza vaccines; comprise Microprojection member, solid film and packing; described Microprojection member comprises a plurality of cuticular Microprojections of patient that are used to pierce through; described solid film and the adjacent setting of described Microprojection member also have at least a influenza vaccines; with the protection vaccine, wherein said packages sealed has been exposed under the radiation so that the Microprojection component sterilization described packing around described Microprojection member sealing.Preferably, described solid film forms by the liquid preparation that curtain coating comprises at least a influenza vaccines, polymeric material, plasticizer, surfactant and volatile solvent.
[00034] In one embodiment of the present invention, the Microprojection member has about at least 10 Microprojections/cm 2, more preferably about at least 200-2000 Microprojection/cm 2Microprojection density.
[00035] in one embodiment, the Microprojection member is made of rustless steel, titanium, Nitinol or similar biocompatible materials.
[00036] in one embodiment, described Microprojection member is made of such as polymeric material non-conductive material.
[00037] replacedly, described Microprojection member can be coated with non-conductive material, such as Parylene , perhaps hydrophobic material is such as Teflon , silicon or other lower-energy material.
[00038] puts on described Microprojection member and can comprise aqueous and non-aqueous preparation with the coating formulation that forms solid-state biocompatible coating.In at least a embodiment of the present invention, described preparation (one or more) comprises at least a influenza vaccines, and it can be dissolved in the biological compatibility carrier or be suspended in the carrier.
[00039] preferably, influenza vaccines are trivalent influenza vaccines.For example, the HA content of every strain in this trivalent vaccine is set at the single body dosage of 15 μ g/ usually, also, and 45 μ g HA total amounts.
[00040] in one embodiment, this system is used for 45 μ g hemagglutinins are delivered to the epidermal area that is rich in APC, and wherein at least 70% influenza vaccines are delivered to described epidermal area.
Description of drawings
[00041] with reference to the accompanying drawings shown in the more specifically description of the preferred embodiment of the invention of example, other features and advantages of the present invention will become apparent, wherein identical Reference numeral is identical parts or the key element of general expression in whole accompanying drawings, wherein:
[00042] Fig. 1 is the part perspective view of a kind of example of Microprojection member;
[00043] Fig. 2 is the perspective view of the Microprojection member shown in Figure 1 according to the present invention, deposits coating on this Microprojection;
[00044] Fig. 3 is the side view that wherein is provided with the keeper of Microprojection member according to the present invention;
[00045] Fig. 4 is the perspective view of keeper shown in Figure 3;
[00046] Fig. 5-the 7th according to microphotograph of the present invention, is used to illustrate postradiation coating pattern;
[00047] Fig. 8 shows according to the present invention the effectiveness of hemagglutinin after different gamma-radiation levels and temperature;
[00048] Fig. 9 shows the effectiveness of the hemagglutinin after different electron beam illumination levels and temperature according to the present invention;
[00049] Figure 10 shows the total protein content of the hemagglutinin that shines in different temperatures according to the present invention;
[00050] Figure 11-the 13rd, the micrograph of the coating pattern according to the present invention after gamma-radiation;
[00051] Figure 14 is selecting the protein content after different exposure doses under the environmental condition according to the present invention;
[00052] Figure 15 is selecting postradiation hemagglutinin effectiveness under the environmental condition according to the present invention;
[00053] Figure 16 and 17 is micrographs of the coating pattern behind oxirane disinfection according to the present invention;
[00054] Figure 18 is using the postradiation protein content of different system parts according to the present invention.
The specific embodiment
[00055] before describing the present invention in detail, is to be understood that to the invention is not restricted to concrete exemplary materials, method or structure, because they can change certainly.Therefore, although can be used to implement the present invention with those many materials and methods similar or that be equal to described herein, preferable material and method are described herein.
[00056] should be appreciated that also term used herein is only used for describing specific embodiment of the present invention, and do not mean that restriction the present invention.
[00057] unless definition has in addition, the technical term of all uses and scientific terminology have the same meaning as one skilled in the art's common sense of the present invention.
[00058] and, no matter all publications, patent and patent application that this paper quotes are above-mentioned or following, this paper is all incorporated by reference with it.
[00059] last, as used in this description and accessory claim, singulative " certain " and " being somebody's turn to do " comprise the indicant of plural number, unless clear and definite regulation is arranged in addition.Therefore, for example, described " antigen " comprises two or more these antigens; " Microprojection " mentioned comprises two or more these Microprojections etc.
Definition
[00060] term " transdermal " refers to send medicament and enters and/or pass skin and be used for part or systemic treatment as used herein.Therefore, term " transdermal " refer to and comprise send in Intradermal, intradermal and the epidermis medicament for example vaccine enter and/or pass skin, for example ionotherapy and phonophoresis are realized via passive diffusion and energy base transdermal delivery for they.
[00061] term " transdermal flow " refers to the speed of transdermal delivery as used herein.
[00062] term used herein " influenza vaccines " is meant that promotion produces the activating agent of immune response to one or more antigens relevant with influenza virus.Preferably, described influenza vaccines comprise division-variation vaccine (split-varion vaccine).More preferably, influenza vaccines comprise one or more unit price hemagglutinin antigen.More preferably, described vaccine is the trivalent influenza vaccines.
[00063] as used herein term " send jointly " refer to before sending influenza vaccines, transdermal flows into before the influenza vaccines and during, transdermal flow into influenza vaccines during, transdermal flows into during the influenza vaccines and afterwards, and/or after transdermal flows into influenza vaccines, the medicament (one or more) of transdermal administration complementarity.In addition, two or more influenza vaccines can be formulated in coating and/or the aqueogel, to realize sending jointly of influenza vaccines.
[00064] should be appreciated that and to be attached in medicament source of the present invention, preparation and/or coating and/or the solid film preparation more than a kind of influenza vaccines, and two or more this antigens of use do not got rid of in the term of use " influenza vaccines ".
[00065] term " Microprojection " or " microprojections " refer to pierce through element as used herein, and it is suitable for piercing through or penetrating live animal, particularly mammal, Ren Lei horny layer more especially, and enter following epidermal area or epidermis and skin corium.
[00066] In one embodiment of the present invention, pierce through element and have length less than 1000 microns outthrust.In further embodiment, pierce through outthrust length that element has for less than 500 microns, be more preferably less than 250 microns.The width that Microprojection further has (being labeled as " W " in Fig. 1) is about 25-500 micron, and thickness is about 10-100 micron.Microprojection can be made different shapes, for example needle-like, blade-like, major part needle-like, borer shape and combination thereof.
[00067] term " Microprojection member " is often referred to and comprises a plurality of microprojection arrays that are used to pierce through cuticular a plurality of Microprojections with array format as used herein.The Microprojection member can prepare by the following method: etching or stamp out a plurality of Microprojections from the thin slice, and Microprojection is folding or bend to outside the described plate plane, form configuration, for example in Fig. 1, show.The Microprojection member also can be by other known way preparation, and for example by forming one or more bands, the edge of each of described band (one or more) has Microprojection, as at U.S. patent No.6, disclosed in 050,988, this paper is all incorporated by reference with it.
[00068] term " coating formulation " means and comprises flowable compositions or the mixture that is used to apply Microprojection and/or its array as used herein.If influenza vaccines are distributed in wherein, then influenza vaccines can be present in the preparation with solution or suspension.
[00069] term " biocompatible coating " and " solid-state coating " mean and comprise " coating formulation " that is essentially solid-state as used herein.
[00070] term used herein " biologic effective dose " or " bioavailability " be meant stimulate or cause required immunity, the normally amount or the rate of the required immune-active agent of useful result.The amount of the immune-active agent that adopts in coating of the present invention is to send the required required amount of immunocompetence dosage of required immune result that obtains.In fact, this can alter a great deal, and specifically depends on specific immune-active agent, the delivery location of being sent, dissolving and the release dynamics that is used for described immune-active agent is delivered to skin histology.
[00071] term used herein " binding agent " is meant and comprises be used to the binding agent that helps described Microprojection member to be held in place on the patient.Usually, described binding agent is diaphragm (patch) form.
[00072] as mentioned above, the present invention generally comprises and be used for making the transdermal delivery system disinfectant method when preparation process finishes.The present invention also comprises the disinfectant delivery system.Transdermal delivery system comprises Microprojection member (perhaps system), and it has a plurality of Microprojections (perhaps its array) that horny layer enters following epidermal area or epidermal area and skin corium that are used to pierce through.Described Microprojection member (or system) also comprises at least one source or the delivery media (that is, biocompatible coating, aqueogel and solid film preparation) of influenza vaccines.Transdermal delivery system is finally sterilized by being exposed under the radiation that is enough to obtain required sterilization assurance level.
[00073] gamma-rays can send by conventional method, for example by adopting cobalt 60 as radiation source.As well known in the skilled person, commercially available cobalt 60 disinfectors produce the exposure rate of about 0.3Gy/hr-9.6Gy/hr.Also can adopt americium 241, exposure rate is about 0.3mGy/hr usually.Other isotope is can be used for sending gamma-rays with required rate.The common rate height than gamma-radiation of electron beam irradiation is such as about 100kGy/hr.In preferred embodiments, close rate is 3.0kGy/hr or bigger, so that obtain to be enough to reach the required processing time minimum of dosage of required sterilisation level.
[00074] finally sterilizing required radiation dose can be by determining based on the conventional method of the required sterilization assurance level (SAL) relevant with the biological load (bioburden) of the apparatus that is sterilized.For example, to require SAL usually be 10 to conventional non-delivery system through the intestinal active pharmaceutical agent -6In other embodiments of the present invention, can specify low biological load for influenza vaccines, this is because the antigen medicament is estimated by bioassay usually, rather than estimates with stricter chromatographic process.In described embodiment, can adopt 10 -3SAL customize radiation dose.As described below, the sterilization requirement of reduction makes can be for described final disinfecting process adopts lower radiation dose, and this helps to keep the antigenicity of influenza vaccines.
[00075] therefore, by with electron beam or radiation gamma system, realized being loaded with the final sterilization of the Microprojection member of influenza vaccines.Proper dosage is about 10-25kGy.Preferably, dosage is about at least 7kGy.More preferably, dosage is about 14kGy.According to the present invention, also can adopt the dosage of about 21kGy.
[00076] preferred, the Microprojection member is sealed in order to protect in the packing of vaccine in disinfecting process.In one embodiment, described packing is the paper tinsel bag.
[00077] in another embodiment of the present invention, the Microprojection member is installed on the keeper ring before in being sealed in described packing, to use together with applicator.
[00078] in other embodiments of the present invention, in packing, comprise binding agent.
[00079] in further embodiment of the present invention, shines the Microprojection member with the stationary flow influenza vaccine at limiting temperature.In one embodiment, the Microprojection member approximately-the temperature irradiation of 78.5-25 ℃.The Microprojection member can be-78.5 ℃ of irradiations under the dry ice condition.In other embodiments, the Microprojection member is in approximately 0-25 ℃ temperature irradiation.In other embodiments, the Microprojection member is in approximately 20-25 ℃ temperature irradiation.
[00080] preferred, influenza vaccines comprise division-variation vaccine.More preferably, influenza vaccines comprise one or more unit price hemagglutinin antigen.More preferably, vaccine is the trivalent influenza vaccines.
[00081] can be about the other information of final disinfectant of other bioactivator referring to common unsettled U. S. application series number 60/687636 (submissions on June 2nd, 2005) and 60/687635 (submission on June 2nd, 2005), incorporated by reference at this full text.
[00082], shows an embodiment that is used for Microprojection member 30 of the present invention referring now to Fig. 1 and 2.As shown in Figure 1, Microprojection member 30 comprises the microprojection array 32 with a plurality of Microprojections 34.Microprojection 34 preferably becomes the direction of an angle of 90 degrees to extend along the fundamental sum sheet material, and described sheet material comprises opening 38 in the illustrated embodiment.In this embodiment, by etching from foil material 36 or stamp out a plurality of Microprojections 34 and described Microprojection 34 is bent to outside sheet material 36 planes, form Microprojection 34.
[00083] in one embodiment of the invention, Microprojection member 30 has about at least 10 Microprojection/cm 2, preferably about at least 200-2000 Microprojection/cm 2Microprojection density.Preferably, the open amount by vaccine is about at least 10 opening/cm on the unit are 2, less than about 2000 openings/cm 2
[00084] as shown, preferably, the outthrust length that Microprojection 34 has is less than 1000 microns.In one embodiment, the outthrust length that Microprojection 34 has is more preferably less than 250 microns less than 500 microns.Preferably, the width that Microprojection 34 also has is about 25-500 micron, and thickness is about 10-100 micron.
[00085] for the biocompatibility that improves Microprojection member 30 (for example making the hemorrhage and inflammation minimum that is applied to behind the patient skin), in further embodiment, preferably, the length that Microprojection 34 has is less than 145 μ m, more preferably, be about 50-145 μ m, more preferably, be about 70-140 μ m.And Microprojection member 30 comprises array, and preferably, the Microprojection density that this array has is greater than 100 Microprojections/cm 2, more preferably, be about 200-3000 Microprojection/cm 2
[00086] Microprojection member 30 can use various metal preparations, for example rustless steel, titanium, Nitinol or similar biocompatible materials.
[00087] according to the present invention, Microprojection member 30 also can be by non-conducting material polymer manufacture for example.
[00088] in addition, the Microprojection member can apply with non-conducting material or hydrophobic material, and described non-conducting material is Parylene for example , described hydrophobic material is Teflon for example , silicon or other low energy material.The hydrophobic material of having mentioned and relevant substrate (for example photoresist) layer is described in U.S. application No.60/484, and in 142, this paper is incorporated by reference with it.
[00089] according to the present invention, adoptable Microprojection member includes, but are not limited to be disclosed in U.S. patent Nos.6, the member in 083,196,6,050,988 and 6,091,975, and this paper is incorporated by reference with it.
[00090] spendable other Microprojection member comprises by using the member of following method preparation according to the present invention: by the etching silicon preparation of use silicon wafer etching technique or by using etched minisize mould to come the moulded plastic preparation, for example be disclosed in U.S. patent No.5,879, member in 326, this paper is incorporated by reference with it.
[00091] according to the present invention, wait that the influenza vaccines that are administered to the host can be contained in the biocompatible coating that is arranged on the Microprojection member 30, be contained in the aqueogel or be contained in biocompatible coating and aqueogel in.Preferably, aqueogel of the present invention comprises water base hydrogel.Hydrogel is owing to having high water content and biocompatibility, so be preferred preparation.Also preferably hydrogel is mixed with the form of gel pack (gel pack).
[00092] in further embodiment, wherein the Microprojection member comprises the solid film preparation that contains vaccine, and influenza vaccines can be contained in biocompatible coating, aqueogel or solid film preparation or all three kinds of delivery media.
[00093] in one embodiment, solid film prepares by the liquid preparation that curtain coating comprises following component: at least a influenza vaccines, polymeric material is such as hetastarch, glucosan, hydroxyethyl-cellulose (HEC), hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), hydroxyethylmethyl-cellulose (HEMC), ethylhydroxyethylcellulose (EHEC), carboxymethyl cellulose (CMC), poly-(vinyl alcohol), poly-(oxirane), poly-(2-hydroxyethyl methacrylate), poly-(positive vinyl pyrrolidone) and pluronics, plasticizer is such as glycerol, propylene glycol and Polyethylene Glycol, surfactant is such as Tween 20 and Tween 80, with volatile solvent such as water, isopropyl alcohol, methanol and ethanol.
[00094] in one embodiment, the liquid preparation that is used to prepare solid film comprises the volatile solvent of 0.1-20 weight % influenza vaccines, 5-40 weight % polymer, 5-40 weight % plasticizer, 0-2 weight % surfactant and surplus.
[00095] in curtain coating with subsequently after the solvent evaporated, forms solid film.
[00096] preferred, influenza vaccines are about 0.1-2 weight % at the liquid preparation content that is used for preparing solid film.
[00097] according to the present invention, at least a influenza vaccines are contained at least a above-mentioned delivery media.The content of influenza vaccines in the Microprojection system that is applied to delivery media and therefore prepares is that the influenza vaccines of delivery treatments effective dose are wanted the required amount of result with acquisition.In fact, it can extensively change according to the seriousness of specific influenza vaccines, site of delivery, disease and desirable therapeutic effects.
[00098] in one embodiment, the Microprojection member comprises biocompatible coating, and this coating comprises at least a influenza vaccines, preferred trivalent hemagglutinin.The sterilization assurance level that the Microprojection parts are finally sterilized required.When piercing through the horny layer of skin, body fluid (for example tissue fluid of intracellular fluid and extracellular fluid) dissolving comprises the coating of vaccine, it is discharged into skin (promptly inject and send) be used for systemic treatment.
[00099] referring now to Fig. 2, shown Microprojection member 31 with Microprojection 34, Microprojection comprises the biocompatible coating 35 of influenza vaccines.According to the present invention, coating 35 can cover each Microprojection 34 partially or completely.For example, coating 35 can be to be positioned at exsiccant patterning coating on the Microprojection 34.Coating 35 also can apply before or after Microprojection 34 forms.
[000100], can coating 35 be put on the Microprojection 34 by multiple known method according to the present invention.Preferably, only coating is applied on those parts that Microprojection member 31 or Microprojection 34 pierce through skin (for example most advanced and sophisticated 39).
[000101] a kind of such painting method comprises immersion coating.Immersion coating also can be described as by Microprojection 34 partly or entirely is immersed in and applies Microprojection in the coating solution.By using partially submerged technology, coating 35 might be limited on the tip 39 of Microprojection 34 only.
[000102] another painting method comprises rolling method, and it uses roller coat mechanism, coating 35 is defined on the tip 39 of Microprojection 34 similarly.Rolling method is disclosed in U.S. application No.10/099,604 (publication No. No.2002/0132054), and this paper is all incorporated by reference with it.As what describe in detail in the application of having mentioned, disclosed rolling method provides slick coating, and during piercing through skin, it is not easy to come off from Microprojection 34.
According to the present invention, Microprojection 34 may further include the device that is used to hold and/or improve coating 35 capacity, for example hole (not show), groove (not showing), surface imperfection thing (not showing) or similar variant, wherein said device has increased surface area, can deposit more substantial coating thereon.
[000104] spendable another kind of painting method comprises spraying in the scope of the invention.According to the present invention, spraying can comprise the aerosol suspension liquid that forms coating composition.In one embodiment, will have drop size is that the aerosol suspension liquid that about 10 to 200 skins rise is sprayed on the Microprojection 34, dry then.
[000105] also can use patterning to apply (pattern coating) and be coated with Microprojection 34.Patterning applies to use and places the lip-deep compartment system of Microprojection to apply deposited liquid.Preferably, institute's deposited liquid amount is 0.1 to 20 to receive liter/Microprojection.The example of the liquid distribution trough of suitable delicate metering is disclosed in U.S. patent Nos.5,916,524; 5,743,960; 5,741,554; With 5,738, in 728, this paper is all incorporated by reference with it.
[000106] also can use ink-jet technology to apply Microprojection coating formulation or solution, described technology has been utilized known electromagnetic valve distributor, optional fluid displacement apparatus and positioner, and it can utilize electric field controls usually.Also can use other liquid distribution technology or similar liquid distribution technique known in the art to apply patterning coating of the present invention from printing industry.
[000107] referring now to Fig. 3 and 4, for storing and applying, preferably Microprojection member 30 is hung in the keeper ring 40 by cohesive lappet (adhesive tab) 6, as applying for No.09/976 at U.S., describe among 762 (the publication number No.2002/0091357), this paper is all incorporated by reference with it.
[000108] after being placed on the Microprojection member in the keeper ring 40, the Microprojection member is put on patient skin.Preferably, use the impact type applicator that the Microprojection member is put on patient skin, for example at unsettled U.S. application No.09/976, describe in 978, this paper is all incorporated by reference with it.As mentioned above, keeper ring 40 preferably before packing through super-dry, thereby reduce the water quantities in Microprojection surrounding air in irradiation process.
[000109] as shown, according to a kind of embodiment of the present invention, be applied to Microprojection member 30 and can comprise aqueous and the non-aqueous preparation that contains at least a influenza vaccines with the coating formulation that forms solid biologic compatibility coating.According to the present invention, described influenza vaccines may be dissolved in the biological compatibility carrier or are suspended in this carrier.
[000110] as known in the field, influenza virus particles is made up of the numerous protein component, and wherein hemagglutinin (HA) is as the main surface antigen of being responsible for introducing the anti-HA antibody of protectiveness in human body.From immunology, influenza A virus is according to two kinds of surface antigens, and HA and neuraminidase (NA) are divided into two hypotypes.Immunity to this antigen especially hemagglutinin has reduced possibility of infection, has reduced the order of severity of disease when taking place to infect.
[000111] antigen property of circulation strain provides the foundation for the Strain of selecting annual vaccine.Each year, influenza vaccines contain the Strain (common two kind As and a kind of B) of three kinds of representatives the influenza virus that the possible whole world is spread in next winter.Influenza A and B can distinguish by its difference of examining in egg and the stromatin.Type A is modal strain, and is responsible to described main human epidemic diseases.Accordingly, influenza vaccines preferably include the trivalent influenza vaccines.For example, the HA content of every strain in the trivalent vaccine is set to the single people's dosage of 15 μ g/ usually, also, and total HA amount of 45 μ g.
[000112] in one embodiment, the influenza vaccines of total man's body dosage, it also is the hemagglutinin of 45 μ g, can be via the microprojection array transdermal delivery of coating to the epidermal area that is rich in APC, also be in the most immunocompetent part of skin, wherein at least 70% influenza vaccines are delivered to described epidermal area.More importantly, it is immunogenic that antigen keeps in skin, thereby cause intensive antibody and the response of serum protective immunity.Other details of relevant suitable influenza vaccine formulation can be referring to common unsettled U. S. application series 11/084631 (submissions on March 18th, 2005) and 11/084635 (submission on March 18th, 2005), and this paper is incorporated by reference with its full text at this.
[000113] the suitable immune response that can constitute vaccine with vaccine antigen helps and increases auxiliary agent and include but not limited to: Fosfalugel (Yamanouchi); Aluminium hydroxide; Algae glucosan (algal glucan): beta glucan; Choleratoxin B subunit: CRL1005:ABA block copolymer, meansigma methods x=8, y=205; The γ inulin: straight chain (non-side chain) β-D (2-〉1) Polyfructose. furan oxygen base (polyfructofuranoxyl)-alpha-D-glucose; Gerbu auxiliary agent: N-acetyl glucosamine-(β 1-4)-N-acetyl group muramyl-L-alanyl-D-glutamine (GMDP), dimethyl two-octadecyl ammonium chloride (DDA), zinc L-proline salt complex (Zn-Pro-8); Imiquimod (imiquimod) (1-(2-methyl-propyl)-1H-imidazoles [4,5-c] quinoline-4-amine; ImmTher TM: N-vinyl glucose amino (acetylglucoaminyl)-N-acetyl group muramyl-L-Ala-D-isoGlu-L-Ala-dipalmitin; MTP-PE liposome: C 59H 108N 6O 19PNa-3H 2O (MTP); Murametide:Nac-Mur-L-Ala-D-GIn-OCH 3Pleuran: beta glucan; QS-21; S-28463:4-amino-a, a-dimethyl-1H-imidazoles [4,5-c] quinoline-1-ethanol; The salvo peptide; VQGEESNDKHCl (IL-1 β 163-171 peptide); And Threonyl-MDP (Termurtide TM): N-acetyl group muramyl-L-Threonyl-D-isoglutamine and interleukin-18, IL-2, IL-1 2, IL-15.Auxiliary agent also comprises the DNA oligonucleotide, such as the oligonucleotide that for example contains CpG.In addition, can adopt the nucleotide sequence of encoding such as IL-18, IL-2, IL-12, IL-15, IL-4, IL10, IFN-and NF Kappa B conditioning signal albumen at the immunomodulating lymphokine.
[000114], can change the amount of auxiliary agent and type to realize the optimization of influenza vaccines stability during the sterilization according to the present invention.
[000115] preferably, the viscosity of coating formulation is less than about 500 centipoises, greater than 3 centipoises.
[000116] In one embodiment of the present invention, coating layer thickness is more preferably less than 10 microns, from the Microprojection surface measurement less than 25 microns.
[000117] required coating layer thickness depends on multiple factor, comprises required dosage and sends the Microprojection density of the required coating layer thickness of described dosage, sheet material unit are, viscosity and the concentration and the selected painting method of coating composition thus.Be applied to coating 35 thickness on the Microprojection 34 and also can change stability with the optimization influenza vaccines.
[000118] in all cases, after having applied coating, coating formulation is dried on the Microprojection 34 by variety of way.In a preferred embodiment of the invention, coated Microprojection member 30 is dry under the environment indoor conditions.But, can adopt all temps and humidity level that coating formulation is dried on the Microprojection.In addition, the member of coating can heat, storage, lyophilizing under vacuum or on the desiccant, solidify drying or similar techniques, to remove residual moisture from coating.
[000119] it should be understood by one skilled in the art that the present invention also can use with different kinds of ions electric osmose therapy or electrotransport system in order to promote transport of drug to pass skin barrier, in this, the present invention is not subjected to the restriction of any way.Exemplary electrotransport drug delivery systems is disclosed in U.S. patent Nos.5, and 147,296,5,080,646,5,169,382 and 5,169,383, with wherein disclosed content is all incorporated by reference.
[000120] term " electrotransport " is instigated useful medicament usually for example vaccine or medicine or prodrug is passed body surface for example skin, mucosa, fingernail etc.The transhipment of medicament is by what apply electromotive force and induce or promote, and it has used electric current, sends medicament or has promoted sending of medicament, perhaps " oppositely " electrotransport, sampling medicament or promoted the sampling of medicament.Can realize that the electrotransport medicament enters human body or transports from human body by variety of way.
[000121] a kind of widely used electrotransport method, ionotherapy relates to the transhipment that electricity is induced charged ion.Electric osmose, the electrotransport method that another relates to the uncharged or neutral charge molecule (for example transdermal sampling glucose) of transdermal transport is included under the electric field influence, and film is passed in the solvent motion that contains medicament.Electroporation, the electrotransport of another type relates to medicament is passed by applying the hole that electric pulse forms to the film, and electric pulse is a high-voltage pulse.
[000122] in many cases, can be simultaneously by the method for carrying out in various degree mentioning more than a kind of.Therefore, in this article, term " electrotransport " has provided its wideest admissible explanation, comprises that electricity is induced or the transportation that improves at least a charged or uncharged medicament or its mixture, and does not consider the specific mechanism (one or more) that in fact medicament transports.In addition, other transportation raising method also can be used for the present invention such as phonophoresis or piezoelectricity apparatus.
Embodiment
[000123] provides following embodiment, so that those skilled in the art can more be expressly understood and implement the present invention.Not will be understood that they limit the scope of the invention, it only is representative elaboration the of the present invention.
Embodiment 1
[000124] preparation of preparation trivalent influenza vaccines and being coated on the microprojection array.The array that applies is placed preparation irradiation on the scintillation glass bottle.Sample is stood dosage under dry ice and room temperature be 7,14 and gamma-radiation and the electron beam irradiation of 21kGy.Adopt the one-way radiation immunodiffusion to measure the array of (SRID) and dihomocinchonine acid albumin mensuration (BCA) assessment band coating at postradiation hemagglutinin content.SRID comprises the formation precipitation zone, interacts at this zone endoantigen and suitable antiserum.The antigen amount that exists in zone that forms and the test formulation is directly proportional.Antigen to be measured is joined in the hole of containing in the described sero-fast agarose gel.Antigen and antiserum interact in the zone around the hole, spread and precipitation.Coomassie blue stain makes can observe described zone intuitively.Antigenic diameter and the reference standard that to test subsequently compare, to quantize antigenic amount.SRID is the method that unique external test influenza vaccines that get the nod are renderd a service.As well known in the skilled person, hemagglutinin effectiveness and immunogenicity have good dependency.
[000125] Fig. 5-7 shows the microcosmic scanned photograph of the pattern at the microprojection array tip that scribbles influenza vaccines.Fig. 5 shows the pattern of the contrast array that does not have irradiation, and Fig. 6 and 7 shows gamma-rays and the postradiation microprojection array of the electron beam tip of using 21kGy respectively.Can find that the shape at the array tip of irradiation is compared with the contrast array with surface flatness, basic not change.This shows that the physical property of coating is not subjected to the negative effect of sterilizing and shining.
[000126] Fig. 8 and 9 shows the SRID measurement result of the microprojection array that shone with gamma-rays and electron beam respectively.Generally speaking, gamma-rays and electron beam irradiation are roughly the same to the influence degree of influenza vaccines, and have all reduced the effectiveness of hemagglutinin, especially when high radiation dose.And the B/Shangdong strain demonstrates the bigger sensitivity to disinfectant program.These results confirm that also exposure dose decline helps to preserve hemagglutinin really and renders a service.For example, when 7kGy, observe loss of effectiveness less than 20%.In addition, this test confirms that irradiation temperature decline has also reduced loss of effectiveness, has obtained optimum under the dry ice condition.
[000127] Figure 10 shows the total protein content through the microprojection array of irradiation.BCA analyzes the water solublity that has also confirmed coating.Just as can be appreciated, the dissolubility that weakens and the protein content of reduction show tangible chemical change have taken place in the bacterin preparation.What deserves to be mentioned is that this studies show that the protein content in each sample recovers fully.Correspondingly, this dissolubility that has shown the vaccine coating does not well change because of illumination procedure.
Embodiment 2
[000128] preparation of preparation trivalent influenza vaccines and being coated on the microprojection array.Sample is stood 7 and the gamma-rays and the electron beam irradiation of 14kGy dosage under the ambient temperature of dry ice and 20-25 ℃.Some microprojection arrays and Merlon keeper ring, binding agent fit together, and are then packed in the paper tinsel bag.Adopt SRID and BCA to estimate the array of band coating at postradiation hemagglutinin content.
[000129] Figure 11-13 has provided the scanning electron photo of the pattern at the microprojection array tip that scribbles influenza vaccines.Figure 11 shows the pattern of the contrast array that does not have irradiation, and Fig. 6 and 7 shows the microprojection array tip of crossing with the radiation gamma of 14kGy respectively in vial and paper tinsel bag.Can find that compare with the contrast array, the shape at the tip of the array that shone and surface flatness significantly do not change.These results have confirmed the result of embodiment 1 report, and the physical features that shows coating is not subjected to the negative effect of sterilisation radiation.
[000130] in addition, the protein that shows in this research of Figure 14 recovers the suitable of (proteinrecovery) and embodiment 1.Particularly, BCA the analysis showed that the dissolubility of vaccine coating does not change because of illumination procedure.
[000131] Zhao She sample also adopts SRID to measure, and the result is suitable among Figure 15.For the sample in being contained in vial, degenerate obviously during at dosage for 14kGy, loss of effectiveness 40% under dry ice, at ambient temperature more than 50%.Because the sample of accepting 7kGy dosage does not have tangible loss of effectiveness, thus dosage influence highly significant.Even the important results that provides is under the high dose of ambient temperature, 14kGy, the effectiveness of assembling and be packaged in the sample in the paper tinsel bag is fully also kept.Correspondingly, this embodiment confirms that the assembling array of packages that scribbles influenza vaccines can finally sterilize effectively.
Embodiment 3
[000132] the same with embodiment 1, the preparation of preparation trivalent influenza vaccines also is coated on the microprojection array.Sample accepts 7 and 14kGy dosage radiation gamma under dry ice and ambient temperature.Microprojection array is packed with each parts of Microprojection system, hits the influence of vaccine stability to estimate these parts contrasts.Sample carries out oxirane disinfection and is non-radiative.Adopt SRID and BCA to estimate the hemagglutinin content of the array of described band coating after sterilization.The packing of this embodiment and sterilization protocol column are in table 1.
Table 1
Group number Packing System unit Exposure dose (kGy) Irradiation temperature
1 The paper tinsel bag Ring, binding agent
2 The paper tinsel bag Ring, binding agent 21 20-25℃
3 The paper tinsel bag Ring, binding agent 21 20-25℃
4 The paper tinsel bag Ring, binding agent 14 20-25℃
5 The paper tinsel bag Binding agent 14 20-25℃
6 The paper tinsel bag Ring 14 20-25℃
7 The paper tinsel bag 14 20-25℃
8 Vial 14 20-25℃
9 Vial Binding agent 14 20-25℃
10 Vial EO
[000133] Figure 16 and 17 shows behind oxirane disinfection the scanning electron photo of different views of the most advanced and sophisticated pattern of microprojection array of the coating of group 10.As shown in the figure, do not observe the obvious deterioration effect of vaccine coating physical features.On the contrary, unacceptable morphology change has taken place such as hPTH in the medicament that hygroscopicity is stronger.Correspondingly, have active agent formulation,, can carry out oxirane disinfection and can not damage coating significantly such as influenza vaccines than agent of low hygroscopicity.
[000134] result who obtains in the foregoing description has been followed the tracks of in the BCA analysis to sample in this research, and the protein content in each system all recovers fully.As mentioned above, this dissolubility that shows the vaccine coating does not change because of irradiation.These find to show equally the chemical composition that irradiation can the appreciable impact influenza vaccine formulation.
[000135] sample that shone has also passed through the SRID analysis, and the result is suitable among Figure 18.This studies confirm that the Microprojection system of packing provides good effectiveness retentivity fully, even when the high exposure dose of 21kGy.Really, the effectiveness retentivity of the group under dry ice 3 only demonstrates minimum loss of effectiveness.This is studied the array that also shows paper tinsel bag packing and compares with vial, and the result improves.Particularly, group 8 and 9 has experienced tangible loss of effectiveness when 14kGy dosage, especially for B/Shangdong and A/Panama strain.
[000136] this embodiment further shows the influence of the parts of Microprojection system to the stability of influenza vaccines in the irradiation process.As organize shown in the result of 5-7, the paper tinsel bag has seemed to provide maximum protection, and binding agent takes second place, and is the keeper ring at last.
[000137] same, the sample that stands oxirane disinfection has kept all effectiveness basically.Therefore, these results show that oxirane can be used for can carrying out disinfection to transdermal influenza vaccines delivery system effectively, and can not render a service the generation adverse effect to physical features or hemagglutinin.
[000138] as above-mentioned embodiment with as described in discussing, have and comprise influenza vaccines and can use method of the present invention finally to sterilize by gamma-radiation or electron beam treatment such as the Microprojection member of the antigenic coating formulation of hemagglutinin, rendeing a service does not almost have or not loss.Preferably, the packing of Microprojection member is used at the described vaccine of final disinfecting process protection.For example, the paper tinsel bag of sealing has significant stablizing effect.Equally preferably, the Microprojection member was installed on the keeper ring before packing and and binding agent assembling.
[000139] in addition, also can in final disinfecting process, reduce goods and degenerate by adjusting temperature or reducing sterilization dose.
[000140] under the situation without departing from the spirit and scope of the present invention, those of ordinary skills can carry out various modifications and change so that itself and various uses and situation adapt to the present invention.Equally, these changes and modification are suitable, proper and are intended to drop within the four corner of equal value of claims.

Claims (32)

1. the transdermal apparatus that is used to send influenza vaccines is carried out final disinfectant method, comprise the steps:
The Microprojection member is provided, described Microprojection member has a plurality of cuticular Microprojections of patient that are used to pierce through, described Microprojection member is provided with biocompatible coating, and described coating is formed by the coating formulation that it is provided with at least a influenza vaccines; With
Described Microprojection member is exposed in the radiation that is selected from gamma-radiation and electron beam, and wherein said radiation is enough to the sterilization assurance level that reaches required.
2. the method for claim 1 further comprises described Microprojection member is sealed in the interior step of packing, and described packing is used to control described Microprojection member environmental condition on every side.
3. the method for claim 2, wherein said packing comprises the paper tinsel bag.
4. the method for claim 2 further is included in the step of hermetically drying agent in the described packing.
5. the method for claim 2 further is included in described Microprojection member is sealed in the step that before described Microprojection member is installed in the described packing on the pre-dry keeper ring.
6. the method for claim 4 further is included in described Microprojection member is sealed in the step that before described Microprojection member is installed in the described packing on the pre-dry keeper ring.
7. the method for claim 2 further is included in the described Microprojection member of sealing before with the described step of packing of inert gas purge.
8. the method for claim 7, wherein said noble gas comprises nitrogen.
9. the method for claim 2, the described Microprojection member of the wherein said exposure step in the radiation approximately-78.5-25 ℃ carries out.
10. the method for claim 2, the described Microprojection member of wherein said exposure carries out at ambient temperature to the step in the radiation.
11. comprising to the step in the radiation, the method for claim 2, the described Microprojection member of wherein said exposure carry about 5-50kGy.
12. comprising to the step in the radiation, the method for claim 2, the described Microprojection member of wherein said exposure carry about 7kGy.
13. comprising to the step in the radiation, the method for claim 2, the described Microprojection member of wherein said exposure carry about 21kGy.
14. comprising with the rate greater than about 3.0kGy/hr to the step in the radiation, the method for claim 2, the described Microprojection member of wherein said exposure carry radiation.
15. the method for claim 2, wherein said sterilization guarantee that level is 10 -6
16. the method for claim 2 further comprises antioxidant is joined step in the described coating formulation.
17. the transdermal apparatus that is used to send influenza vaccines is carried out final disinfectant method, comprises the steps:
The Microprojection member is provided, described Microprojection member has a plurality of cuticular Microprojections of patient that are used to pierce through, described Microprojection member is provided with biocompatible coating, and described coating is formed by the coating formulation that it is provided with at least a influenza vaccines; With
With the interior described Microprojection member of package encapsulation that desiccant is arranged, described packing is with nitrogen purging and be used to control environmental condition around the described Microprojection member; With
Described Microprojection member is exposed in the radiation that is selected from gamma-radiation and electron beam, and wherein said radiation is enough to the sterilization assurance level that reaches required.
18. the method for claim 17 further is included in described Microprojection member is sealed in the step that before described Microprojection member is installed in the described packing on the pre-dry keeper ring.
19. the method for claim 17, the described Microprojection member of wherein said exposure comprises the radiation of carrying about 7-21kGy dosage to the step in the radiation.
20. the method for claim 19, the described Microprojection member of wherein said exposure carries out at ambient temperature to the step in the radiation.
21. the method for claim 17, wherein said influenza vaccines keep about at least 96% initial purity.
22. the method for claim 21, wherein said influenza vaccines keep about at least 98% initial purity.
23. the transdermal apparatus that is used to send influenza vaccines is carried out final disinfectant method, comprises the steps:
The Microprojection member is provided, described Microprojection member has a plurality of cuticular Microprojections of patient that are used to pierce through, described Microprojection member is provided with biocompatible coating, and described coating is formed by the coating formulation that it is provided with at least a influenza vaccines;
Described Microprojection member is sealed in the packing, and described packing is with nitrogen purging and be used to control environmental condition around the described Microprojection member; With
Described Microprojection member is exposed in the electron beam irradiation, and wherein said radiation is enough to the sterilization assurance level that reaches required.
24. the transdermal apparatus that is used to send influenza vaccines is carried out final disinfectant method, comprises the steps:
The Microprojection member is provided, described Microprojection member has a plurality of cuticular Microprojections of patient that are used to pierce through, described Microprojection member is provided with biocompatible coating, and described coating is formed by the coating formulation that it is provided with at least a influenza vaccines; With
Described Microprojection member is placed the packing that is used for the condition of controling environment;
Reduce the moisture in the described packing;
With the described Microprojection member of described package encapsulation; With
Described Microprojection member is exposed in the radiation that is selected from gamma-radiation and electron beam, and wherein said radiation is enough to the sterilization assurance level that reaches required.
25. be used to send the transdermal system of influenza vaccines, comprise:
The Microprojection member comprises a plurality of cuticular Microprojections of patient that are used to pierce through, and described Microprojection member is provided with biocompatible coating, and described coating is formed by the coating formulation that it is provided with at least a influenza vaccines; With
Packing, it is with nitrogen purging and be used to control the environmental condition of sealing around the described Microprojection member;
Wherein said packages sealed is exposed in the radiation so that described Microprojection member is carried out disinfection.
26. the system of claim 25 further comprises with described Microprojection member being sealed in desiccant in the described packing together.
27. the system of claim 25, wherein said Microprojection member is installed on the pre-dry keeper ring.
28. the system of claim 25, wherein said packaging nitrogen purging.
29. the system of claim 25, wherein said packing comprises the paper tinsel bag.
30. the system of claim 25, wherein said influenza vaccines comprise the trivalent influenza vaccines.
31. be used to send the transdermal system of influenza vaccines, comprise:
The Microprojection member comprises a plurality of cuticular Microprojections of patient that are used to pierce through;
Aqueogel with at least a influenza vaccines, wherein said aqueogel and described Microprojection member are communicated with; With
Packing, it is with inert gas purge and be used to control the environmental condition of sealing around the described Microprojection member;
Wherein said packages sealed is exposed in the radiation with the described Microprojection member of sterilizing.
32. be used to send the transdermal system of influenza vaccines, comprise:
The Microprojection member comprises a plurality of cuticular Microprojections of patient that are used to pierce through;
The solid film that adjacent described Microprojection member is provided with, wherein said solid film forms by the liquid preparation that curtain coating comprises at least a influenza vaccines, polymeric material, plasticizer, surfactant and volatile solvent; With
Packing, it is with inert gas purge and be used to control the environmental condition of sealing around the described Microprojection member;
Wherein said packages sealed is exposed in the radiation with the described Microprojection member of sterilizing.
CNA2006800192630A 2005-06-02 2006-06-01 Method for terminal sterilization of transdermal delivery devices Pending CN101189030A (en)

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CA2610245A1 (en) 2006-12-07
AU2006252342A1 (en) 2006-12-07
CA2610626A1 (en) 2006-12-07
EP1888126A1 (en) 2008-02-20
EP1885405A1 (en) 2008-02-13
WO2006130868A1 (en) 2006-12-07
WO2006130826A1 (en) 2006-12-07
US20060275170A1 (en) 2006-12-07
AU2006252377A1 (en) 2006-12-07
US20060280644A1 (en) 2006-12-14

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